GENE-THERAPY WITH MODIFIED TUMOR-CELLS ENABLES T-CELL ACTIVATION BY STIMULATING PATHWAYS REQUIRED FOR SIGNAL-TRANSDUCTION

The expression of a variety of stimulatory molecules by tumor cells ca n lead to tumor rejection and the development of systemic immunity by T cells. The fact that some tumor cells naturally express such determi nants leads to the hypothesis that progressive tumor growth may be a r eflection of problems with the host immune system. To test this, we co mpared the signal-transducing ability of T cells from mice inoculated with parental tumors (PTB) with that of T cells from mice immunized wi th IL-2-secreting tumor cells (ITB). Our results demonstrated that fol lowing T-cell activation, higher total kinase activity was associated with the signal-transducing zeta chain in ITB mice compared with PTB m ice. Western blotting following stimulation of T cells with parental o r genetically engineered IL-2-secreting, B7(+) tumor cells revealed in creased protein tyrosine phosphorylation in lysates derived from ITB c ompared with PTB T cells, demonstrating that tumor-derived IL-2 could influence signaling. Taken together, the findings are consistent with the hypothesis that tumor-derived IL-2 preserves the signal-transducin g ability of immunocompetent T cells, but is ineffective when they are immunosuppressed. These results suggest that IL-2-secreting tumor cel l vaccines might be useful as adjuvant therapy to prevent the outgrowt h of micrometastases, following tumor resection, once immune function has normalized.